Wang Zhaoxuan, Wang Cheng, Zhao Shilei, Gu Chundong
Department of Thoracic Surgery, The First Affiliated Hospital of Dalian Medical University, Dalian, China.
Department of Thoracic Surgery, Xishan People's Hospital Of Wuxi City, Wuxi Branch of Zhongda Hospital Southeast University, Wuxi, China.
Front Immunol. 2025 Jun 6;16:1606125. doi: 10.3389/fimmu.2025.1606125. eCollection 2025.
Lung adenocarcinoma (LUAD) is characterized by metabolic and immune heterogeneity, driving tumor progression and therapy resistance. While G protein-coupled receptors (GPCR) signaling is known to regulate metabolism and immunity in cancers, its role in LUAD remains poorly defined. This study explores the influence of GPCR signaling on LUAD metabolism and immune landscape.
We performed non-negative matrix factorization (NMF) clustering of GPCR signaling genes in TCGA-LUAD cohort to identify distinct molecular subgroups. A prognostic model was developed based on GPCR signaling genes using least absolute shrinkage and selection operator (LASSO) analysis and Cox regression. Differentially expressed genes were analyzed for metabolic pathway enrichment and immune infiltration. In addition, key genes within GPCR signaling were identified and validated through functional assays.
NMF clustering based on GPCR signaling identified three subgroups in LUAD, with cluster 3 exhibiting poorer overall survival and significant enrichment in multiple prognostic associated metabolism pathways including purine, pyrimidine, glyoxylate and dicarboxylate metabolism. Then, we developed a GPCRscore prognostic model and validated across multiple cohorts, which effectively stratified LUAD patients into distinct risk groups. High-risk LUAD patients had an immunosuppressive microenvironment and activated metabolic reprogramming. ADM was identified as a key gene in the high-risk group, correlating with tumor stage, immune suppression, and resistance to immunotherapy. Clinically, ADM was highly expressed in tumor tissues and shows elevated concentrations in the peripheral blood of patients with advanced-stage LUAD. Subsequently, we demonstrated that knock-down of ADM in LUAD cells impaired their proliferation, migration, and invasion, while also reducing the angiogenic potential of endothelial cells . Adrenomedullin promoted LUAD progression in a murine metastasis model. Further, adrenomedullin inhibited CD8 T cells proliferation, induced exhaustion, and impaired cytotoxic function. Finally, drug sensitivity and cell viability analysis showed LUAD patients with high levels of ADM exhibited sensitivity to the treatment of Staurosporine and Dasatinib.
In summary, this study reveals the pivotal role of GPCR signaling particularly mediated by ADM in orchestrating metabolic reprogramming and immune modulation in LUAD. ADM emerges as a potential predictive biomarker and therapeutic target, offering valuable implications for optimizing strategies.
肺腺癌（LUAD）具有代谢和免疫异质性，这推动了肿瘤进展和治疗耐药性。虽然已知G蛋白偶联受体（GPCR）信号传导可调节癌症中的代谢和免疫，但它在LUAD中的作用仍不清楚。本研究探讨了GPCR信号传导对LUAD代谢和免疫格局的影响。
我们对TCGA-LUAD队列中的GPCR信号基因进行非负矩阵分解（NMF）聚类，以识别不同的分子亚组。使用最小绝对收缩和选择算子（LASSO）分析和Cox回归，基于GPCR信号基因开发了一个预后模型。分析差异表达基因的代谢途径富集和免疫浸润情况。此外，通过功能试验鉴定并验证了GPCR信号传导中的关键基因。
基于GPCR信号传导的NMF聚类在LUAD中识别出三个亚组，其中第3组总体生存率较差，并且在包括嘌呤、嘧啶、乙醛酸和二羧酸代谢在内的多个预后相关代谢途径中显著富集。然后，我们开发了一个GPCRscore预后模型并在多个队列中进行验证，该模型有效地将LUAD患者分层为不同的风险组。高危LUAD患者具有免疫抑制微环境并激活了代谢重编程。ADM被确定为高危组中的关键基因，与肿瘤分期、免疫抑制和免疫治疗耐药性相关。临床上，ADM在肿瘤组织中高表达，并且在晚期LUAD患者的外周血中浓度升高。随后，我们证明在LUAD细胞中敲低ADM会损害其增殖、迁移和侵袭能力，同时还会降低内皮细胞的血管生成潜力。肾上腺髓质素在小鼠转移模型中促进LUAD进展。此外，肾上腺髓质素抑制CD8 T细胞增殖，诱导耗竭，并损害细胞毒性功能。最后，药物敏感性和细胞活力分析表明，ADM水平高的LUAD患者对星形孢菌素和达沙替尼治疗敏感。
总之，本研究揭示了GPCR信号传导，特别是由ADM介导的信号传导在协调LUAD中的代谢重编程和免疫调节中的关键作用。ADM成为一种潜在的预测生物标志物和治疗靶点，为优化治疗策略提供了有价值的启示。
